Cardiac hypertrophy occurs in response to increased mechanical load and through the action of several hormones and mediators (Sugden and Clerk, 1998). It involves enhanced protein synthesis, cardiomyocyte growth and cytoskeletal reorganization, and is often associated with interstitial fibrosis (Sugden and Clerk, 1998). The mitogen-activated protein kinase (MAPK)-cascade, consisting of Raf1 (rapid growing fibro sarcoma), MEK1/2 (mitogen-activated protein kinase kinases) and ERK1/2 (extracellular signal-regulated kinases), plays a prominent role in cardiac hypertrophy (Sugden and Clerk, 1998).
Activation of the cascade begins with activation of Raf1, which leads to sequential phosphorylation and activation of MEK1/2 and then ERK1/2. MEK1/2 activates ERK1/2 by dual phosphorylation of the threonine- and tyrosine-residues in the TEY-motif of the activation loop (183-185 in mouse ERK2). ERK2 can autophosphorylate at Tyr185, but phosphorylation of both Thr183 and Tyr185 by MEK1/2 is required for full activation (Muslin, 2005). However, the mechanisms regulating the MAPK cascade and thereby leading to cardiac hypertrophy are largely unknown.